{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T07:36:01Z","timestamp":1791272161775,"version":"4.1.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Heart Failure"],"published-print":{"date-parts":[[2016,1]]},"abstract":"<jats:sec>\n            <jats:title>Background\u2014<\/jats:title>\n            <jats:p>\n              Diabetic heart disease is associated with tetrahydrobiopterin oxidation and high arginase activity, leading to endothelial nitric oxide synthase dysfunction. Sepiapterin (SEP) is a tetrahydrobiopterin precursor, and\n              <jats:sc>l<\/jats:sc>\n              -citrulline (\n              <jats:sc>l<\/jats:sc>\n              -Cit) is converted to endothelial nitric oxide synthase substrate,\n              <jats:sc>l<\/jats:sc>\n              -arginine. Whether SEP and\n              <jats:sc>l<\/jats:sc>\n              -Cit are effective at reducing diabetic heart disease is not known. The present study examined the effects of SEP and\n              <jats:sc>l<\/jats:sc>\n              -Cit on diabetic cardiomyopathy and ischemia\/reperfusion injury in obese type 2 diabetic mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods and Results\u2014<\/jats:title>\n            <jats:p>\n              Db\/db and C57BLKS\/J mice at 6 to 8 weeks of age received vehicle, SEP, or\n              <jats:sc>l<\/jats:sc>\n              -Cit orally alone or in combination for 8 weeks. Cardiac function was evaluated with echocardiography. Db\/db mice displayed hyperglycemia, obesity, and normal blood pressure and cardiac function compared with C57BLKS\/J mice at 6 to 8 weeks of age. After vehicle treatment for 8 weeks, db\/db mice had reduced ejection fraction, mitral\n              <jats:italic>E<\/jats:italic>\n              \/\n              <jats:italic>A<\/jats:italic>\n              ratio, endothelium-dependent relaxation of coronary arteries, tetrahydrobiopterin concentrations, ratio of endothelial nitric oxide synthase dimers\/monomers, and nitric oxide levels compared with vehicle-treated C57BLKS\/J mice. These detrimental effects of diabetes mellitus were abrogated by co-administration of SEP and\n              <jats:sc>l<\/jats:sc>\n              -Cit. Myocardial infarct size was increased, and coronary flow rate and \u00b1d\n              <jats:italic>P<\/jats:italic>\n              \/d\n              <jats:italic>t<\/jats:italic>\n              were decreased during reperfusion in vehicle-treated db\/db mice subjected to ischemia\/reperfusion injury compared with control mice. Co-administration of SEP and\n              <jats:sc>l<\/jats:sc>\n              -Cit decreased infarct size and improved coronary flow rate and cardiac function in both C57BLKS\/J and db\/db mice.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>\n              Co-administration of SEP and\n              <jats:sc>l<\/jats:sc>\n              -Cit limits diabetic cardiomyopathy and ischemia\/reperfusion injury in db\/db mice through a tetrahydrobiopterin\/endothelial nitric oxide synthase\/nitric oxide pathway.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circheartfailure.115.002424","type":"journal-article","created":{"date-parts":[[2016,1,14]],"date-time":"2016-01-14T05:49:06Z","timestamp":1452750546000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":48,"title":["Chronic Co-Administration of Sepiapterin and\n            <scp>l<\/scp>\n            -Citrulline Ameliorates Diabetic Cardiomyopathy and Myocardial Ischemia\/Reperfusion Injury in Obese Type 2 Diabetic Mice"],"prefix":"10.1161","volume":"9","author":[{"given":"Shelley L.","family":"Baumgardt","sequence":"first","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Paterson","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten M.","family":"Leucker","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Fang","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David X.","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeljko J.","family":"Bosnjak","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Warltier","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy R.","family":"Kersten","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD (T.M.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi-Dong","family":"Ge","sequence":"additional","affiliation":[{"name":"From the Department of Anesthesiology (S.L.B., M.P., Z.J.B., D.C.W., J.R.K., Z.-D.G.), Department of Pediatrics (J.F.), Department of Medicine (D.X.Z.), Department of Physiology (Z.J.B.), and Department of Pharmacology and Toxicology (D.C.W., J.R.K.), Medical College of Wisconsin, Milwaukee; and Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD 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